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Meg Mangin R.N.
Research Team (on leave)
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Posted: Mon Mar 6th, 2006 01:04 |
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Why should I avoid hormone supplementation?
All the steroid hormones (depending on dose) have the potential to interfere with Benicar’s control of VDR and PPARgamma and it's enabling effect on the immune system.
How Benicar Helps the Immune System
1,25-dihydroxyvitamin-D (calcitriol) is a secosteroid hormone. It’s most important function is to bind to a receptor called the VDR (Vitamin D Receptor) and mediate the transcription of DNA, triggered by signaling proteins, like Nuclear-Factor-kappa-B. The VDR is also expressed in over 30 different tissues throughout the body (including the nucleus of phagocytic cells of the immune system) and plays an important function regulating many other hormones, including PTH, the androgens and those from the thyroid. http://autoimmunityresearch.org/hormones-bw.pdf
In the absence of Th1 inflammatory disease, 1,25-D binds to the VDR to dampen down runaway inflammation and allow the immune system to function properly. However, intra-phagocytic bacteria interfere with this process causing excess 1,25-D to be produced which inhibits the immune system from killing these bacteria.
PPAR (Peroxisome Proliferator-Activated Receptor) gamma is a nuclear transcription factor that controls key genes involved in fatty acid metabolism and energy homeostasis.
Dr. Marshall’s recent work with molecular modeling has shown that Olmesartan (at Marshall Protocol doses) blocks the VDR and PPARgamma from binding to 1,25-D, reducing excess 1,25-D which allows the immune system to function normally again.
Steroid hormones are molecules produced and secreted by endocrine glands in the body. These hormones are released in the blood stream and travel to other parts of the body where they bring about specific responses from specific cells. Steroid hormones are derived from cholesterol and are lipid-soluble molecules.
Steroid hormones cause changes within a cell by first passing through the cell membrane of the target cell.
Once inside the cell each steroid hormone primarily binds with its specific receptor in the cytoplasm of the target cell. The receptor-bound-steroid-hormone then translocates into the nucleus of the cell. The steroid-receptor complex causes the production of messenger RNA (mRNA) molecules from DNA genes through a process called transcription. The mRNA molecules are then transported to the ribosomes. The mRNA molecules code for the production of proteins through a process called translation.
Steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestagens. (Vitamin D derivatives are a sixth closely related hormone system with homologous receptors, though technically sterols rather than steroids.)
Principal natural human steroid hormones are:
Glucocorticoids
-cortisol
Mineralocorticoids
-aldosterone
Sex steroids
-Androgens
-testosterone
-dehydroepiandrosterone (DHEA)
-dehydroepiandrosterone sulfate (DHEAS)
-androstenedione
-dihydrotestosterone (DHT)
Estrogens
-estradiol
-estrone
-estriol
Progestagens
-progesterone
The principal sterol hormone:
Vitamin D derivatives
-calcitriol
A variety of synthetic steroids have also been contrived. Most are steroids but some non-steroidal molecules can interact with the steroid receptors because of a similarity of shape. Some synthetic steroids are weaker, some much stronger, than the natural steroids whose receptors they activate.
Some examples of synthetic steroid hormones:
• Glucocorticoids: prednisone, dexamethasone, triamcinolone
• Mineralocorticoid: fludrocortisone
• Androgens: oxandrolone, decadurabolin (also known as anabolic steroids)
• Estrogens: diethylstilbestrol (DES)
• Progestins: norethindrone, medroxyprogesterone acetate
• Vitamin D: dihydrotachysterol
Molecular modeling has also revealed how steroid hormones dock into nuclear receptors and block the transcription process.
Molecular modeling shows that Prednisolone is a very strong Vitamin D Receptor (VDR) antagonist. This is how prednisone stops the actions of NuclearFactor-kappaB p65, a key transcription protein, which is a cofactor for VDR. Although blocking this protein (essential to the immune system) reduces inflammation, it also causes relapses and many, severe adverse effects (including hyperglycemia and bone degeneration.
HRT (Hormone Replacement Therapy)
Molecular modeling shows that progesterone also blocks VDR and PPARgamma with a high affinity. Our assumption is that all the steroid hormones (depending on dose) have the potential to interfere with Benicar’s control of VDR and PPARgamma.
Therefore, we recommend that steroid hormone supplementation be avoided. If your blood tests revealed a deficiency, this is likely the result of your Th1 inflammation and replacing a hormone simply to bolster the blood level to a presumed physiologic level will do nothing to change your abnormal cellular metabolism. The body will only make further adjustments in a futile attempt to maintain cellular homeostasis.
The VDR is clearly important to a lot of different functions of the human body.. It is the balance, the homeostasis, that keeps the body operating. Homeostasis amongst an almost imponderable number of variables.
Supplementation in the presence of disease is futile and may be counterproductive. The blood level may not accurately reflect the paracrine level and supplementation may cause negative changes as the body attempts to maintain cellular homeostasis. Sort of "It's not nice to fool Mother Nature".
If you have intolerable symptoms of a hormone deficiency and your doctor orders supplementation, standard (low) doses of prescription hormone medication, less than a few milligrams per day in most cases, will probably not interfere with the immune system. It will be advantageous to wean off this supplementation as soon as symptoms allow.
The higher the dose, the more likelihood that any of the steroid hormones, including those typically used for Hormone Replacement Therapy and birth control, will interfere with Benicar's control of VDR and PPARgamma.
In general, any concentration of synthetic progesterone or estrogen under 1 milligram per day is not likely to displace any of the key immune hormones from their target receptors.
Bio-identical (natural) hormones have a lower bioavailability than the common synthetic forms and equivalent doses are, therefore, higher. Bio-identical progesterone is usually ordered 50-100mg twice daily and bio-identical estrogen/s is usually ordered 1-4mg twice daily.
"In many ways the estrogen receptors are complementary to the VDR, and to the receptors active in the immune system. For example, it is believed that the gene for the VDR itself is transcribed by the estrogen-related receptor alpha (ESRRA), and we know (with good certainty) that the ESRRA gene is transcribed by the VDR.
So I am less worried about estrogen. Progesterone is the one that is a member of the mix of hormones that strike the balance which drives the receptors active in the immune system: VDR, PPAR gamma, PPAR alpha, PPAR delta, GlucoCorticoid, MineralCorticoid, Progesterone, Androgen (testosterone), Thyroid alpha 1 and Thyroid beta 1.
My suggestion would be to wean a steroid down slowly, and see what the effect is, bit by bit..."
"There is a big difference between a body's hormonal control system producing a hormone under feedback control, and an attempt to change the operation of the control system by supplying exogenous drug (HRT). Another example is the use of exogenous prednisone or cortisol to try and modulate the immune system - it is fraught with secondary problems."
..Trevor..
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone and should also be avoided.
DHEA
"Taking DHEA supplements directly affects the operation of the Nuclear Receptors, and will delay or prevent recovery from Th1 disease. DHEA is a steroid, with actions very similar to corticosteroids, like prednisone. Although it is palliative, and reduces herx, it does that at the cost of slowing recovery and increasing the risk of complications from steroid use. You will need to wean off DHEA. Since this is a steroid, even though it is sold OTC, please remember to wean. A good idea is to follow the suggestions in the "Weaning from Prednisone" FAQ. You will need Doc to help you monitor the recovery of your normal adrenal function."
Here is a paper which shows how DHEA is linked to VDR.
http://tinyurl.com/yob8j6
The Type 1 nuclear receptors transcribe genes through a delicate balance of endogenous hormones. None of these hormones can be supplemented externally without affecting the body's ability to heal itself. The molecular biology makes this quite clear, and even the consensus opinion of a million physicians cannot change the way our biology works."
..Trevor..
See Carol's experience with DHEA returning to normal on the MP
Human Growth Hormone (HGH)
All the steroid hormones weave a delicate balance between each other. If you look at the Brahmachary et al paper I cite about the antimicrobial peptides, you will find that even the progesterone and androgen (testosterone) receptors are responsible expression of a large number of antimicrobial peptides, and therefore modulate the innate immune system.
I haven't specifically tested HGH to see what it affects most, but I did find that all the steroids affect all the Type 1 nuclear receptors, to greater and lesser extents. It is a homeostasis, a balance.
Haven't you even wondered why a disproportionate number of sportsmen end up with Sarcoidosis? ..Trevor..
Birth Control Pills (click)
It is suggested that you take your newly prescribed birth control pills for one menstrual cycle to see how that hormonal change makes you feel. Then start the Benicar blockade as per the Phase One Guideline. A few women have reported problems with hormonal adjustment when they started the MP while they were pre-menstrual but most women do not have a problem with this.
Please consult your doctor regarding this suggestion and ask him/her to monitor your hormonal levels as you progress on the MP to make sure that the birth control pills continue to prevent ovulation. (The MP is contraindicated for pregnant and lactating women.)
Your doctor will consider the risk/benefit ratio of hormone supplements as s/he manages your treatment plan. Your ability to tolerate the MP and your symptom resolution will help guide decisions regarding hormone supplementation.
Women’s Chart of Hormone Doses
Testosterone
"Testosterone is one of the nuclear hormones, along with 1,25-D, cortisol, aldosterone, progesterone, corticosterone, estrogen, and the thyroid hormone which make up the delicate balance of Type 1 nuclear receptor activators which govern gene transcription for most of the body's antimicrobial peptides, and many of the key proteins.
Testosterone activates the Androgen Nuclear Receptor, which is responsible for transcribing the DNA of many of the genes which give rise to anti-microbial peptides, the body's defense against pathogens. You really don't want to play with the body's Nuclear Hormones in any way, shape or form."
Testosterone is an immunosuppressive steroid that forms one of the interplay of hormones which set up the delicate balance between the Nuclear Receptors which allows your body, and immune system, to transcribe genes, and function correctly. As your body continues to heal, the testosterone will get back to its level in a 'healthy' person. You don't want to be supplementing any of the hormones, in the same way that it is pointless trying to force-fit the Vitamin D hormone into your body."
..Trevor..
Men’s Chart of Hormone Doses
Prescription medications needed for symptom relief which are NOT on the Meds to Avoid List, may be continued. Please use them only if needed and try to wean from them as symptoms improve. Monitor symptoms and reduce or eliminate medications or supplements as symptoms resolve.
If your progress on the MP is hampered in any way, then you should reexamine your medications.
Your body's ability to assimilate supplemented hormones 'normally' will be enhanced as your Th1 inflammation resolves.
For more information, please see:
"Common Angiotensin Receptor Blockers may directly modulate the immune system via VDR, PPAR and CCR2b" Theor Biol Med Model. 2006 Jan 10;3(1):1
PMID: 16403216 [PubMed - as supplied by publisher]
Overview of Steroid Hormones.
Classification of Steroid Hormones
How Steroid Hormones Work
"Visiting Professor" lecture at the Federal Drug Administration's Center for Drug Evaluation and Reserach on Mar.7, 2006 in Bethesda, MD.
Molecular genomics offers new insight into the exact mechanism of action of common drugs - ARBs, Statins, and Corticosteroids. A 'RealVideo 9' version is available online at:
http://autoimmunityresearch.org/fda-visiting-professor-7mar06.ram
The original DVD of the presentation can be requested from:
http://autoimmunityresearch.org/fdacder.htm
You will find a copy of the FDA Designation approval in this file: http://www.fda.gov/orphan/designat/alldes.rtf
"Marshall TG: Molecular genomics offers new insight into the exact mechanism of action of common drugs - ARBs, Statins, and Corticosteroids. FDA CDER Visiting Professor presentation, FDA Biosciences Library, Accession QH447.M27 2006"
You may request a copy of that transcript from:
FDA Biosciences Library,
U.S. Food & Drug Administration
5600 Fishers Lane Rm 11B40 HFD-230
Rockville, MD 20857
See also Cognitive dysfunction in women with Chronic Fatigue Syndrome: examining the role of the endometrium, the nuclear receptors, and antimicrobial peptides
Last edited on Tue Aug 5th, 2008 04:32 by Meg Mangin R.N.
____________________
Nothing contained in this site is or should be considered, or used as a substitute for, medical advice, diagnosis or treatment by your physician.
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Meg Mangin R.N.
Research Team (on leave)
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Posted: Fri Jan 19th, 2007 00:45 |
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(filelink)
Members experiences on the MP
DHEA returns to normal
According to my most recent lab test, the DHEA has almost returned to “normal”.
I found Dr Marshall's comments helpful:
--Verification that dehydroepiandrosterone (DHEA) is a hormonal steroid, and its expression is affected by the Th1 disease process.
--Confirmation that hormonal rebalancing (by your body) is an essential part of the process leading to recovery.
I think the normalization of my DHEA blood test over my time on the MP is consistent with this second point and further evidence of my progress.
~Carol
Dr Marshall:
a chart of where Dehydroepiandrosterone fits into the scheme of things, you will find it here:
http://www.genome.ad.jp/kegg/pathway/map/map00150.html
Period Pain
It was suggested to me increasing Benicar in preperation for my period - last time I did it it worked a treat.. decreased cramps & symptoms (which are usually increased around my period) by about 50%. I went to Q4H a day before and kept it up til day 3 of my period. ~ Nat
Vaginal bleeding
-Disease-related lesions in the female genitalia can cause abnormal bleeding. I can understand your concern because this was one of my persistent complaints during my long battle with what was eventually diagnosed as sarcoidosis. Here are published examples:
Incidental Granulomatous Inflammation of the Uterus (You will be able to view the document after you register, but registration is free.)
Premenopausal metrorrhagia as a symptom of sarcoidosis.
Endometrial sarcoidosis as a cause of postmenopausal bleeding. A case report.
Hormonal fluctuations can cause this abnormal bleeding. See Dr. Marshall's diagram of hormonal fluctuations related to changes in 1,25-D.
Assuming this is immunopathology, have you tried following any of the steps Aussie Barb outlined in her post to you on April 23?
Take a look at Medline's information because you can review the medical questions usually asked when this problem arises. It may help you discuss and evaluate this with your doctors. ~Belinda
Last edited on Fri Sep 5th, 2008 20:00 by Meg Mangin R.N.
____________________
Nothing contained in this site is or should be considered, or used as a substitute for, medical advice, diagnosis or treatment by your physician.
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